Therapeutic combination

ABSTRACT

This invention relates to pharmaceutical combinations of amlodipine or a pharmaceutically acceptable acid addition salt thereof and atorvastatin or a pharmaceutically acceptable salt thereof, kits containing such combinations and methods of using such combinations to treat subjects suffering from angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia and to treat subjects presenting with symptoms of cardiac risk, including humans. This invention also relates to additive and synergistic combinations of amlodipine and atorvastatin whereby those synergistic combinations are useful in treating subjects suffering from angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia and those subjects presenting with symptoms of cardiac risk, including humans.

This invention relates to pharmaceutical combinations of amlodipine andpharmaceutical acceptable acid addition salts thereof and atorvastatinand pharmaceutically acceptable salts thereof, kits containing suchcombinations and methods of using such combinations to subjectssuffering from angina pectoris, atherosclerosis, combined hypertensionand hyperlipidemia and to treat subjects presenting with symptoms ofcardiac risk, including humans. This invention also relates to additiveand synergistic combinations of amlodipine and atorvastatin wherebythose additive and synergistic combinations are useful in treatingsubjects suffering from angina pectoris, atherosclerosis, combinedhypertension and hyperlipidemia and those subjects presenting withsymptoms or signs of cardiac risk including humans.

BACKGROUND OF THE INVENTION

The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) tomevalonate is an early and rater-limiting step in the cholesterolbiosynthetic pathway. This step is catalyzed by the enzyme HMG-CoAreductase. Statins inhibit HMG-CoA reductase from catalyzing thisconversion. As such, statins are collectively potent lipid loweringagents.

Atorvastatin calcium, disclosed in U.S. Pat. No. 5,273,995, which isincorporated herein by reference, is currently sold as Lipitor® and hasthe formula

Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA.As such, atorvastatin calcium is a potent lipid lowering compound. Thefree carboxylic acid form of atorvastatin exists predominantly as thelactone of the formula

and is disclosed in U.S. Pat. No. 4,681,893, which is incorporatedherein by reference.

Amlodipine and related dihydropyridine compounds are disclosed in U.S.Pat. No. 4,572,909, which is incorporated herein by reference, as potentanti-schemic and antihypertensive agents. U.S. Pat. No. 4,879,303, whichis incorporated herein by reference, discloses amlodipinebenzenesulfonate salt (also termed amlodipine besylate). Amlodipine andamlodipine besylate are potent and long lasting calcium channelblockers. As such, amlodipine, amlodipine besylate and otherpharmaceutically acceptable acid addition salts of amlodipine haveutility as antihypertensive agents and as antischemic agents. Amlodipineand its pharmaceutically acceptable acid addition salts are alsodisclosed in U.S. Pat. No. 5,155,120 as having utility in the treatmentof congestive heart failure. Amlodipine besylate is currently sold asNorvasc®. Amlodipine has the formula

Atherosclerosis is a condition characterized by irregularly distributedlipid deposits in the intima of arteries, including coronary, carotidand peripheral arteries. Atherosclerotic coronary heart disease(hereinafter termed “CHD”) accounts for 53% of all deaths attributableto a cardiovascular event. CHD accounts for nearly one-half (about$50-60 billion) of the total U.S. cardiovascular healthcare expendituresand about 6% of the overall national medical bill each year. Despiteattempts to modify secondary risk factors such as, inter alia, smoking,obesity and lack of exercise, and treatment of dyslipidemia with dietarymodification and drug therapy, CHD remains to most common cause of deathin the United States.

High levels of blood cholesterol and blood lipids are conditionsinvolved in the onset of atherosclerosis. It is well known thatinhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAreductase) are effective in lowering the level of blood plasmacholesterol, especially low density lipoprotein cholesterol (LDL-C), inman (Brown and Goldstein, New England Journal of Medicine, 1981, 305,No. 9, 515-517). It has now been established that lowering LDL-C levelsaffords protection from coronary heart disease (see, e.g., TheScandinavian Simvastatin Survival Study Group: Randomised trial ofcholesterol lowering in 4444 patients with coronary heart disease: theScandinavian Simvastatin Survival Study (4S), Lancet, 1994, 344,1383-89; and Shepherd. J. et al., Prevention of coronary heart diseasewith pravastatin in men with hypercholesterolemia, New England Journalof Medicine, 1995, 333, 1301-07).

Angina pectoris is a severe constricting pain in the chest, oftenradiating from the precordium to the left shoulder and down the leftarm. Often angina pectoris is due to ischemia of the heart and isusually caused by coronary disease.

Currently the treatment of symptomatic angina pectoris variessignificantly from country to country. In the U.S., patients who presentwith symptomatic, stable angina pectoris are frequently treated withsurgical procedures or PTCA. Patients who undergo PTCA or other surgicalprocedures designed to treat angina pectoris frequently experiencecomplications such as restenosis. This restenosis may be manifestedeither as a short term proliferative response to angioplasty-inducedtrauma or as long term progression of the atherosclerotic process inboth graft vessels and angioplastied segments.

The symptomatic management of angina pectoris involves the use of anumber of drugs, frequently as a combination of two or more of thefollowing classes: beta blockers, nitrates and calcium channel blockers.Most, if not all, of these patients require therapy with a lipidlowering agent as well. The National Cholesterol Education Program(NCEP) recognizes patients with existing coronary artery disease as aspecial class requiring aggressive management of raised LDL-C.

Amlodipine helps to prevent myocardial ischemia in patients withexertional angina pectoris by reducing Total Peripheral Resistance, orafterload, which reduces the rate pressure product and thus myocardialoxygen demand at any particular level of exercise. In patients withvasospastic angina pectoris, amlodipine has been demonstrated to blockconstriction and thus restore myocardial oxygen supply. Further,amlodipine has been shown to increase myocardial oxygen supply bydilating the coronary arteries.

Hypertension frequently coexists with hyperlipidemia and both areconsidered to be major risk factors for developing cardiac diseaseultimately resulting in adverse cardiac events. This clustering of riskfactors is potentially due to a common mechanism. Further, patientcompliance with the management of hypertension is generally better thanpatient compliance with hyperlipidemia. It would therefore beadvantageous for patients to have a single therapy which treats both ofthese conditions.

Coronary heart disease is a multifactorial disease in which theincidence and severity are affected by the lipid profile, the presenceof diabetes and the sex of the subject. Incidence is also affected bysmoking and left ventricular hypertrophy which is secondary tohypertension. To meaningfully reduce the risk of coronary heart disease,it is important to manage the entire risk spectrum. For example,hypertension intervention trials have failed to demonstrate fullnormalization in cardiovascular mortality due to coronary heart disease.Treatment with cholesterol synthesis inhibitors in patients with andwithout coronary artery disease reduces the risk of cardiovascularmorbidity and mortality.

The Framingham Heart Study, an ongoing prospective study of adult menand women, has shown that certain risk factors can be used to predictthe development of coronary heart disease. (see Wilson et al., Am. J.Cardiol. 1987, 59(14):91G-94G). These factors include age, gender, totalcholesterol level, high density lipoprotein (HDL) level, systolic bloodpressure, cigarette smoking, glucose intolerance and cardiac enlargement(left ventricular hypertrophy on electrocardiogram, echocardiogram orenlarged heart on chest X-ray). Calculators and computers can easily beprogrammed using a multivariate logistic function that allowscalculation of the conditional probability of cardiovascular events.These determinations, based on experience with 5,209 men and womenparticipating in the Framingham study, estimate coronary artery diseaserisk over variable periods of follow-up. Modeled incidence rates rangefrom less than 1% to greater than 80% over an arbitrarily selected sixyear interval. However, these rates are typically less than 10% andrarely exceed 45% in men and 25% in women.

Kramsch et al., Journal of Human Hypertension (1995) (Suppl. 1), 53-59disclose the use of calcium channel blockers, including amlodipine, totreat atherosclerosis. That reference further suggests thatatherosclerosis can be treated with a combination of amlodipine and alipid lowering agent. Human trials have shown that calcium channelblockers have beneficial effects in the treatment of earlyatherosclerotic lesions. (see, e.g., Lichtlen, P. R. et al., Retardationof angiographic progression o coronary artery disease by nifedipine,Lancet, 1990, 335, 1109-13; and Waters, D. et al., A controlled clinicaltrial to assess the effect of a calcium channel blocker on theprogression of coronary atherosclerosis, Circulation, 1990, 82,1940-53.) U.S. Pat. No. 4,681,893 discloses that certain statins,including atorvastatin, are hypolipidemic agents and as such are usefulin treating atherosclerosis. Jukema et al., Circulation, 1995 (Suppl.1), 1-197, disclose that there is evidence that calcium channel blockersact synergistically in combination with lipid lowering agents (e.g.,HMG-CoA reductase inhibitors), specifically pravastatin. Orekhov et al.,Cardiovascular Drugs and Therapy, 1997, 11, 350 disclose the use ofamlodipine in combination with lovastatin for the treatment ofatherosclerosis.

SUMMARY OF THE INVENTION

This invention is directed to a pharmaceutical composition, hereinaftertermed “Composition A” comprising:

-   -   a. an amount of amlodipine or a pharmaceutically acceptable acid        addition salt thereof;    -   b. an amount of atorvastatin or a pharmaceutically acceptable        salt thereof; and    -   c. a pharmaceutically acceptable carrier or diluent.

This invention is particularly directed to a pharmaceutical composition,hereinafter termed “Composition AA”, of Composition A comprisingamlodipine besylate.

This invention is more particularly directed to a pharmaceuticalcomposition, hereinafter termed “Composition AB”, of Composition AAcomprising the hemicalcium salt of atorvastatin.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition B”, for use with a second pharmaceuticalcomposition for achieving a antihypertensive effect and a hypolipidemiceffect in a mammal suffering from hypertension and hyperlipidemia, whicheffects are greater than the sum of the antihypertensive andhypolipidemic effects achieved by administering said first and secondpharmaceutical compositions separately and which second pharmaceuticalcomposition comprises an amount of amlodipine or a pharmaceuticallyacceptable acid addition salt thereof and a pharmaceutically acceptablecarrier or diluent, said first pharmaceutical composition comprising anamount of atorvastatin or a pharmaceutically acceptable salt thereof anda pharmaceutically acceptable carrier or diluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition BA”, of Composition Bwherein said second pharmaceutical composition comprises amlodipinebesylate.

This invention is more particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition BB”, of Composition BAcomprising the hemicalcium salt of atorvastatin.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition C”, for use with a second pharmaceuticalcomposition for achieving a anthypertensive effect and a hypolipidemiceffect in a mammal suffering from hypertension and hyperlipidemia, whicheffects are greater than the sum of the antihypertensive andhypolipidemic effects achieved by administering said first and secondpharmaceutical compositions separately and which second pharmaceuticalcomposition comprises an amount of atorvastatin or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier ordiluent, said first pharmaceutical composition comprising an amount ofamlodipine or a pharmaceutically acceptable acid addition salt thereofand a pharmaceutically acceptable carrier or diluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition CA”, of Composition Ccomprising amlodipine besylate.

This invention is more particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition CB”, of Composition CAwherein said second pharmaceutical composition comprises the hemicalciumsalt of atorvastatin.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition D”, for use with a second pharmaceuticalcomposition for achieving a antihypertensive effect and a hypolipidemiceffect in a mammal suffering from hypertension and hyperlipidemia, whicheffects are greater than the antihypertensive and hypolipidemic effectsachieved by administering said first or second pharmaceuticalcompositions separately and which second pharmaceutical compositioncomprises an amount of atorvastatin or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier or diluent, saidfirst pharmaceutical composition comprising an amount of amlodipine or apharmaceutically acceptable acid addition salt thereof and apharmaceutically acceptable carrier or diluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition DA”, of Composition Dcomprising amlodipine besylate.

This invention is more particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition DB”, of Composition DAwherein said second pharmaceutical composition comprises the hemicalciumsalt of atorvastatin.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition E”, for use with a second pharmaceuticalcomposition for achieving a antihypertensive effect and a hypolipidemiceffect in a mammal suffering from hypertension and hyperlipidemia, whicheffects are greater than the antihypertensive and hypolipidemic effectsachieved by administering said first or second pharmaceuticalcompositions separately and which second pharmaceutical compositioncomprises an amount of amlodipine or a pharmaceutically acceptable acidaddition salt thereof and a pharmaceutically acceptable carrier ordiluent, said first pharmaceutical composition comprising an amount ofatorvastatin or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier or diluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition EA”, of Composition Ewherein said second pharmaceutical composition comprises amlodipinebesylate.

This invention is more particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition EB” of Composition EAcomprising the hemicalcium salt of atorvastatin.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition F”, for use with a second pharmaceuticalcomposition for achieving an antianginal effect in a mammal sufferingfrom angina pectoris, which effect is greater than the sum of theantiangina effects achieved by administering said first and secondpharmaceutical compositions separately and which second pharmaceuticalcomposition comprises an amount of atorvastatin or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier ordiluent, said first pharmaceutical composition comprising an amount ofamlodipine or a pharmaceutically acceptable acid addition salt thereofand a pharmaceutically acceptable carrier or diluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition FA”, of Composition Fcomprising amlodipine besylate.

This invention is more particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition FB”, of Composition FAwherein said second pharmaceutical composition comprises the hemicalciumsalt of atorvastatin.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition G”, for use with a second pharmaceuticalcomposition for achieving an antianginal effect in a mammal sufferingfrom angina pectoris, which effect is greater than the sum of theantiangina effects achieved by administering said first and secondpharmaceutical compositions separately and which second pharmaceuticalcomposition comprises an amount of amlodipine or a pharmaceuticallyacceptable acid addition salt thereof and a pharmaceutically acceptablecarrier or diluent, said first pharmaceutical composition comprising anamount of atorvastatin or a pharmaceutically acceptable salt thereof anda pharmaceutically acceptable carrier or diluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition GA”, of Composition Gwherein said second pharmaceutical composition comprises amlodipinebesylate.

This invention is more particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition GB”, of Composition Gcomprising the hemicalcium salt of atorvastatin.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition H”, for use with a second pharmaceuticalcomposition for achieving an antianginal effect in a mammal, sufferingfrom angina pectoris, which effect is greater than the antianginaleffects achieved by administering said first or second pharmaceuticalcompositions separately and which second pharmaceutical compositioncomprises an amount of atorvastatin or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier or diluent, saidfirst pharmaceutical composition comprising an amount of amlodipine or apharmaceutically acceptable acid addition salt thereof and apharmaceutically acceptable carrier or diluent acceptable carrier ordiluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition HA”, of Composition Hcomprising amlodipine besylate.

This invention is more particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition HB”, of Composition HAwherein said second pharmaceutical composition comprises the hemicalciumsalt of atorvastatin.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition J”, for use with a second pharmaceuticalcomposition for achieving an antianginal effect in a mammal sufferingfrom angina pectoris, which effect is greater than the antianginaleffects achieved by administering said first or second pharmaceuticalcompositions separately and which second pharmaceutical compositioncomprises an amount of amlodipine or a pharmaceutically acceptable acidaddition salt thereof and a pharmaceutically acceptable carrier ordiluent, said first pharmaceutical composition comprising an amount ofatorvastatin or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier or diluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition JA”, of Composition Jwherein said second pharmaceutical composition comprises amlodipinebesylate.

This invention is more particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition JB”, of Composition JAcomprising the hemicalcium salt of atorvastatin.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition K”, for use with a second pharmaceuticalcomposition for achieving an antiatherosclerotic effect in a mammal,which effect is greater than the sum of the antiatherosclerotic effectsachieved by administering said first and second pharmaceuticalcompositions separately and which second pharmaceutical compositioncomprises an amount of amlodipine or a pharmaceutically acceptable acidaddition salt thereof and a pharmaceutically acceptable carrier ordiluent, said first pharmaceutical composition comprising an amount ofatorvastatin or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier or diluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition KA”, of Composition Kwherein said second pharmaceutical composition comprises amlodipinebesylate.

This invention is more particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition KB”, of Composition KAcomprising the hemicalcium salt of atorvastatin.

This invention is still more particularly directed to a composition,hereinafter termed “Composition KC”, of Composition KB wherein saidantiatherosclerotic effect is manifested by a slowing of the progressionof atherosclerotic plaques.

This invention is still more particularly directed to a composition ofComposition KC wherein said progression of atherosclerotic plaques isslowed in coronary arteries.

This invention is also particularly directed to a composition ofComposition KB wherein said progression of atherosclerotic plaques isslowed in carotid arteries.

This invention is also particularly directed to a composition ofComposition KB wherein said progression of atherosclerotic plaques isslowed in the peripheral arterial system.

This invention is more particularly directed to a composition,hereinafter termed “Composition KD”, of Composition KB wherein saidantiatherosclerotic effect is manifested by a regression ofatherosclerotic plaques.

This invention is still more particularly directed to a composition ofComposition KD wherein said regression of atherosclerotic plaques occursin coronary arteries.

This invention is also particularly directed to a composition ofComposition KD wherein said regression of atherosclerotic plaques occursin carotid arteries.

This invention is also particularly directed to a composition ofComposition KD wherein said regression of atherosclerotic plaques occursin the peripheral arterial system.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition L”, for use with a second pharmaceuticalcomposition for achieving an antiatherosclerotic effect in a mammal,which effect is greater than the sum of the antiatherosclerotic effectsachieved by administering said first and second pharmaceuticalcompositions separately and which second pharmaceutical compositioncomprises an amount of atorvastatin or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier or diluent, saidfirst pharmaceutical composition comprising an amount of amlodipine or apharmaceutically acceptable acid addition salt thereof and apharmaceutically acceptable carrier or diluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition LA”, of Composition Lcomprising amlodipine besylate.

This invention is more particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition LB”, of Composition LAwherein said second pharmaceutical composition comprises the hemicalciumsalt of atorvastatin.

This invention is still more particularly directed to a composition,hereinafter termed “LC”, of Composition LB wherein saidantiatherosclerotic effect is manifested by a slowing of the progressionof atherosclerotic plaques.

This invention is still more particularly directed to a composition ofComposition LC wherein said progression of atherosclerotic plaques isslowed in coronary arteries.

This invention is also particularly directed to a composition ofComposition LC wherein said progression of atherosclerotic plaques isslowed in carotid arteries.

This invention is also particularly directed to a composition ofComposition LC wherein said progression of atherosclerotic plaques isslowed in the peripheral arterial system.

This invention is more particularly directed to a composition,hereinafter termed “Composition LD”, of Composition LB wherein saidantiatherosclerotic effect is manifested by a regression ofatherosclerotic plaques.

This invention is still more particularly directed to a composition ofComposition LD wherein said regression of atherosclerotic plaques occursin coronary arteries.

This invention is also particularly directed to a composition ofComposition LD wherein said regression of atherosclerotic plaques occursin carotid arteries.

This invention is also particularly directed to a composition ofComposition LD wherein said regression of atherosclerotic plaques occursin the peripheral arterial system.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition M”, for use with a second pharmaceuticalcomposition for achieving an antiatherosclerotic effect in a mammal,which effect is greater than the antiatherosclerotic effects achieved byadministering said first or second pharmaceutical compositionsseparately and which second pharmaceutical composition comprises anamount of atorvastatin or a pharmaceutically acceptable salt thereof anda pharmaceutically acceptable carrier or diluent, said firstpharmaceutical composition comprising an amount of amlodipine or apharmaceutically acceptable acid addition salt thereof and apharmaceutically acceptable carrier or diluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition MA”, of Composition Mcomprising amlodipine besylate.

This invention is more particularly directed to a first pharmaceuticalcomposition hereinafter termed “Composition MB”, of Composition MAwherein said second pharmaceutical composition comprises the hemicalciumsalt of atorvastatin.

This invention is still more particularly directed to a composition,hereinafter termed “Composition MC”, of Composition MB wherein saidantiatherosclerotic effect is manifested by a slowing of the progressionof atherosclerotic plaques.

This invention is still more particularly directed to a composition ofComposition MC wherein said progression of atherosclerotic plaques isslowed in coronary arteries.

This invention is also particularly directed to a composition ofComposition MC wherein said progression of atherosclerotic plaques isslowed in carotid arteries.

This invention is also particularly directed to a composition ofComposition MC wherein said progression of atherosclerotic plaques isslowed in the peripheral arterial system.

This invention is more particularly directed to a composition,hereinafter termed “Composition MD”, of Composition MB wherein saidantiatherosclerotic effect is manifested by a regression ofatherosclerotic plaques.

This invention is still more particularly directed to a composition ofComposition MD wherein said regression of atherosclerotic plaques occurin coronary arteries.

This invention is also particularly directed to a composition ofComposition MD wherein said regression of atherosclerotic plaques occursin carotid arteries.

This invention is also particularly directed to a composition ofComposition MD wherein said regression of atherosclerotic plaques occursin the peripheral arterial system.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition N”, for use with a second pharmaceuticalcomposition for achieving an antiatherosclerotic effect in a mammal,which effect is greater than the antiatherosclerotic effects achieved byadministering said first or second pharmaceutical compositionsseparately and which second pharmaceutical composition comprises anamount of amlodipine or a pharmaceutically acceptable acid addition saltthereof and a pharmaceutically acceptable carrier or diluent, said firstpharmaceutical composition comprising an amount of atorvastatin or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or diluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition NA”, of Composition Nwherein said second pharmaceutical composition comprises amlodipinebesylate.

This invention is more particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition NB”, of Composition NAcomprising the hemicalcium salt of atorvastatin.

This invention is still more particularly directed to a composition,hereinafter termed, “Composition NC”, of Composition NB wherein saidantiatherosclerotic effect is manifested by a slowing of the progressionof atherosclerotic plaques.

This invention is still more particularly directed to a composition ofComposition NC wherein said progression of atherosclerotic plaques isslowed in coronary arteries.

This invention is also particularly directed to a composition ofComposition NC wherein said progression of atherosclerotic plaques isslowed in carotid arteries.

This invention is also particularly directed to a composition ofComposition NC wherein said progression of atherosclerotic plaques isslowed in the peripheral arterial system.

This invention is more particularly directed to a composition,hereinafter termed “Composition ND”, of Composition NB wherein saidantiatherosclerotic effect is manifested by a regression ofatherosclerotic plaques.

This invention is still more particularly directed to a composition ofComposition ND wherein said regression of atherosclerotic plaques occursin coronary arteries.

This invention is also particularly directed to a composition ofComposition ND wherein said regression of atherosclerotic plaques occursin carotid arteries.

This invention is also particularly directed to a composition ofComposition ND wherein said regression of atherosclerotic plaques occursin the peripheral arterial system.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition P”, for use with a second pharmaceuticalcomposition for managing cardiac risk in a mammal at risk of sufferingan adverse cardiac event, which effect is greater than the sum of thecardiac risk management effects achieved by administering said first andsecond pharmaceutical compositions separately and which secondpharmaceutical composition comprises an amount of atorvastatin or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or diluent, said first pharmaceutical compositioncomprising an amount of amlodipine or a pharmaceutically acceptable acidaddition salt thereof and a pharmaceutically acceptable carrier ordiluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition PA”, of Composition Pcomprisig amlodipine besylate.

This invention is more particularly directed to a first pharmaceuticalcomposition of Composition PA wherein said second pharmaceuticalcomposition comprises the hemicalcium salt of atorvastatin.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition Q”, for use with a second pharmaceuticalcomposition for managing cardiac risk in a mammal at risk of sufferingan adverse cardiac event, which effect is greater than the sum of thecardiac risk management effects achieved by administering said first andsecond pharmaceutical compositions separately and which secondpharmaceutical composition comprises an amount of amlodipine or apharmaceutically acceptable acid addition salt thereof and apharmaceutically acceptable carrier or diluent, said firstpharmaceutical composition comprising an amount of atorvastatin or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or diluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition QA”, of Composition Qwherein said second pharmaceutical composition comprises amlodipinebesylate.

This invention is more particularly directed to a first pharmaceuticalcomposition of Composition QA comprising the hemicalcium salt ofatorvastatin.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition R”, for use with a second pharmaceuticalcomposition for managing cardiac risk in a mammal at risk of sufferingan adverse cardiac event, which effect is greater than the cardiac riskmanagement effects achieved by administering said first or secondpharmaceutical compositions separately and which second pharmaceuticalcomposition comprises an amount of atorvastatin or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier ordiluent, said first pharmaceutical composition comprising an amount ofamlodipine or a pharmaceutically acceptable acid addition salt thereofand a pharmaceutically acceptable carrier or diluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition RA”, of Composition Rcomprising amlodipine besylate.

This invention is more particularly directed to a first pharmaceuticalcomposition of Composition RA wherein said second pharmaceuticalcomposition comprises the hemicalcium salt of atorvastatin.

This invention is also directed to a first pharmaceutical composition,hereinafter termed “Composition S”, for use with a second pharmaceuticalcomposition for managing cardiac risk in a mammal at risk of sufferingan adverse cardiac event, which effect is greater than the cardiac riskmanagement effects achieved by administering said first or secondpharmaceutical compositions separately and which second pharmaceuticalcomposition comprises an amount of amlodipine or a pharmaceuticallyacceptable acid addition salt thereof and a pharmaceutically acceptablecarrier or diluent, said first pharmaceutical composition comprising anamount of atorvastatin or a pharmaceutically acceptable salt thereof anda pharmaceutically acceptable carrier or diluent.

This invention is particularly directed to a first pharmaceuticalcomposition, hereinafter termed “Composition SA”, of Composition Swherein said second pharmaceutical composition comprises amlodipinebesylate.

This invention is more particularly directed to a first pharmaceuticalcomposition of Composition S comprising the hemicalcium salt ofatorvastatin.

This invention is also directed to a kit, hereinafter termed “Kit A”,for achieving a therapeutic effect in a mammal comprising:

-   -   a. an amount of amlodipine or a pharmaceutically acceptable acid        addition salt thereof and a pharmaceutically acceptable carrier        or diluent in a first unit dosage form;    -   b. an amount of atorvastatin or a pharmaceutically acceptable        salt thereof and a pharmaceutically acceptable carrier or        diluent in a second unit dosage form; and    -   c. container means for containing said first and second dosage        forms.

This invention is particularly directed to a kit, hereinafter termed“Kit AA”, of Kit A comprising amlodipine besylate.

This invention is more particularly directed to a kite hereinaftertermed “Kit AB”, of Kit AA comprising the hemicalcium salt ofatorvastatin.

This invention is still more particularly directed to a kit, hereinaftertermed “Kit AC”, of Kit AB wherein said therapeutic effect is treatmentof hypertension and hyperlipidemia.

This invention is still more particularly directed to a kit, hereinaftertermed “Kit AD”, of Kit AB wherein said therapeutic effect is treatmentof angina pectoris.

This invention is also particularly directed to a kit, hereinaftertermed “Kit AE”, of Kit AB wherein said therapeutic effect is managementof cardiac risk.

This invention is also particularly directed to a kit hereinafter termed“Kit AF”, of Kit AB wherein said therapeutic effect is treatment ofatherosclerosis.

This invention is still more particularly directed to a kit hereinaftertermed “Kit AG”, of Kit AF wherein said treatment of atherosclerosisslows the progression of atherosclerotic plaques.

This invention is further directed to a kit hereinafter termed “Kit AH”,of Kit AG wherein said progression of atherosclerotic plaques is slowedin coronary arteries.

This invention is still further directed to a kit, hereinafter termed“Kit AJ”, of Kit AG wherein said progression of atherosclerotic plaquesis slowed in carotid arteries.

This invention is still further directed to a kit, hereinafter termed“Kit AK”, of Kit AG wherein said progression of atherosclerotic plaquesis slowed in the peripheral arterial system.

This invention is still further directed to a kit, hereinafter termed“Kit AL”, of Kit AF wherein said treatment of atherosclerosis causes theregression of atherosclerotic plaques.

This invention is still further directed to a kit of Kit AL wherein saidregression of atherosclerotic plaques occurs in coronary arteries.

This invention is still further directed to a kit of Kit AL wherein saidregression of atherosclerotic plaques occurs in carotid arteries.

This invention is still further directed to a kit of Kit AL wherein saidregression of atherosclerotic plaques occurs in the peripheral arterialsystem.

This invention is also directed to a method, hereinafter termed “MethodA”, for treating a mammal in need of therapeutic treatment comprisingadministering to said mammal

-   -   (a) an amount of a first compound, said first compound being        amlodipine or a pharmaceutically acceptable acid addition salt        thereof; and    -   (b) an amount of a second compound, said second compound being        atorvastatin or a pharmaceutically acceptable salt thereof;        wherein said first compound and said second compound are each        optionally and independently administered together with a        pharmaceutically acceptable carrier or diluent.

This invention is particularly directed to a method, hereinafter MethodB, of Method A comprising amlodipine besylate.

This invention is more particularly directed to a method, hereinaftertermed “Method C”, of Method B comprising the hemicalcium salt ofatorvastatin.

This invention is still more particularly directed to a method,hereinafter termed “Method D”, of Method A wherein said first compoundand said second compound are administered simultaneously.

This invention is still more particularly directed to a method,hereinafter termed “Method E”, of Method A wherein said first compoundand said second compound are administered sequentially in either order.

This invention is also particularly directed to a method, hereinaftertermed “Method F”, of Method C wherein said first compound and saidsecond compound are administered simultaneously.

This invention is further directed to a method, hereinafter termed“Method G”, of Method C wherein said first compound and said secondcompound are administered sequentially in either order.

This invention is still further directed to a method of Method A whereinsaid therapeutic treatment comprises antihypertensive treatment andantihyperlipidemic treatment.

This invention is still further directed to a method of Method F whereinsaid therapeutic treatment comprises anthypertensive treatment andantihyperlipidemic treatment.

This invention is still further directed to a method of Method G whereinsaid therapeutic treatment comprises antihypertensive treatment andantihyperlipidemic treatment.

This invention is further directed to a method of Method A wherein saidtherapeutic treatment comprises antianginal treatment.

This invention is further directed to a method of Method F wherein saidtherapeutic treatment comprises antianginal treatment.

This invention is further directed to a method of Method G wherein saidtherapeutic treatment comprises antianginal treatment.

This invention is further directed to a method of Method A wherein saidtherapeutic treatment comprises cardiac risk management.

This invention is further directed to a method of Method F wherein saidtherapeutic treatment comprises cardiac risk management.

This invention is further directed to a method of Method G wherein saidtherapeutic treatment comprises cardiac risk management.

This invention is further directed to a method of Method A wherein saidtherapeutic treatment comprises antiatherosclerotic treatment.

This invention is further directed to a method of Method F wherein saidtherapeutic treatment comprises antiatherosclerotic treatment.

This invention is further directed to a method of Method G wherein saidtherapeutic treatment comprises antiatherosclerotic treatment.

Amlodipine is a racemic compound due to the symmetry at position 4 ofthe dihydropyridine ring. The R and S enantomers may be prepared asdescribed by Arrowsmith et al., J. Med. Chem., 1986, 29, 1696. Thecalcium channel blocking activity of amlodipine is substantiallyconfined to the S(−) isomer and to the racemic mixture containing theR(+) and S(−) forms. (see International Patent Application NumberPCT/EP94/02697). The R(+) isomer has little or no calcium channelblocking activity. However, the R(+) isomer is a potent inhibitor ofsmooth muscle cell migration. Thus, the R(+) isomer is useful in thetreatment or prevention of atherosclerosis. (see International PatentApplication Number PCT/EP95/00847). Based on the above, a skilled personcould choose the R(+) isomer, the S(−) isomer or the racemic mixture ofthe R(+) isomer and the S(−) isomer for use in the combination of thisinvention.

Where used herein, the term “cardiac risk” means the likelihood that asubject will suffer a future adverse cardiac event such as, e.g.,myocardial infarction, cardiac arrest, cardiac failure, cardiacischaemia. Cardiac risk is calculated using the Framingham Risk Equationas set forth above. The term “cardiac risk management” means that therisk of future adverse cardiac events is substantially reduced.

DETAILED DESCRIPTION OF THE INVENTION

The pharmaceutical compositions of this invention comprise amlodipine ora pharmaceutically acceptable acid addition salt thereof and/oratorvastatin or a pharmaceutically acceptable salt thereof.

Amlodipine may readily be prepared as described in U.S. Pat. No.4,572,909 which is incorporated herein by reference. Amlodipinebesylate, which is currency sold as Norvasc®, may be prepared asdescribed in U.S. Pat. No. 4,879,303, which is incorporated herein byreference. Amlodipine and amlodipine besylate are potent and longlasting calcium channel blockers.

The expression “pharmaceutically-acceptable acid addition salts” isintended to define but is not limited to such salts as thehydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate,hydrogen phosphate, dihydrogenphosphate, acetate, besylate, succinate,citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate)salts.

Other acid addition salts of amlodipine may be prepared by reacting thefree base form of amlodipine with the appropriate acid. When the salt isof a monobasic acid (e.g., the hydrochloride, the hydrobromide, thep-toluenesulfonate, the acetate), the hydrogen form of a dibasic acid(e.g., the hydrogen sulfate, the succinate) or the dihydrogen form of atribasic acid (e.g., the dihydrogen phosphate, the citrate), at leastone molar equivalent and usually a molar excess of the acid is employed.However when such salts as the sulfate, the hemisuccinate, the hydrogenphosphate or the phosphate are desired, the appropriate and exactchemical equivalents of acid will generally be used. The free base ofamlodipine and the acid are usually combined in a co-solvent from whichthe desired salt precipitates, or can be otherwise isolated byconcentration and/or addition of a non-solvent.

Atorvastatin may readily be prepared as described in U.S. Pat. No.4,681,892, which is incorporated herein by reference. The hemicalciumsalt of atorvastatin, which is currently sold as Lipitor®, may readilybe prepared as described in U.S. Pat. No. 5,273,995, which isincorporated herein by reference.

The expression “pharmaceutically acceptable salts” includes bothpharmaceutically acceptable acid addition salts and pharmaceuticallyacceptable cationic salts. The expression “pharmaceutically-acceptablecationic salts” is intended to define but is not limited to such saltsas the alkali metal salts, (e.g. sodium and potassium), alkaline earthmetal salts (e.g. calium and magnesium), aluminum salts, ammonium salts,and salts with organic amines such as benzathine(N,N′-dibenzylelenediamine), choline, diethanolamine, ethylenediamne,meglumine (N-methylglucamine), benethamine (N-benzylphenetamine),diethylamne, piperazne, tromethamine(2-amino-2-hydroxymethyl-1,3-propanediol) and procaine. The expression“pharmaceutically-acceptable acid addition salts” is intended to definebut is not limited to such salts as the hydrochloride, hydrobromide,sulfate, hydrogen sulfate, phosphate, hydrogen phosphate,dihydrogenphosphate, acetate, succinate, citrate, methanesulfonate(mesylate) and p-toluenesulfonate (tosylate) salts.

Other pharmaceutically-acceptable cationic salts of atorvastatin may bereadily prepared by reacting the free acid form of atorvastatin with anappropriate base, usually one equivalent, in a co-solvent. Typical basesare sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride,potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine,choline, diethanolamine, piperazine and trompethamine. The salt isisolated by concentration to dryness or by addition of a non-solvent. Inmany cases, salts are preferably prepared by mixing a solution of theacid with a solution of a different salt of the cation (e.g., sodium orpotassium ethylhexanoate, magnesium oleate) and employing a solvent(e.g., ethyl acetate) from which the desired cationic salt precipitates.The salts may also be isolated by concentrating the reaction solutionand/or by adding a non-solvent.

The acid addition salts of atorvastatin may be readily prepared byreacting the free base form of atorvastatin with the appropriate acid.When the salt is of a monobasic acid (e.g., the hydrochloride, thehydrobromide, the p-toluenesulfonate, the acetate), the hydrogen form ofa dibasic acid (e.g., the hydrogen sulfate, the succinate) or thedihydrogen form of a tribasic acid (e.g., the dihydrogen phosphate, thecitrate), at least one molar equivalent and usually a molar excess ofthe acid is employed. However when such salts as the sulfate, thehemisuccinate, the hydrogen phosphate or the phosphate are desired, theappropriate and exact chemical equivalents of acid will generally beused. The free base and the acid are usually combined in a co-solventfrom which the desired salt precipitates, or can be otherwise isolatedby concentration and/or addition of a non-solvent.

In addition, amlodipine, pharmaceutically acceptable acid addition saltsthereof, atorvastatin and pharmaceutically acceptable salts thereof mayoccur as hydrates or solvates. Said hydrates and solvates are alsowithin the scope of the invention.

The pharmaceutical combinations and methods of this invention are alladapted to therapeutic use as agents in the treatment ofatherosclerosis, angina pectoris, and a condition characterized by thepresence of both hypertension and hyperlipidemia in mammals,particularly humans. Further, since these diseases and conditions areclosely related to the development of cardiac disease and adversecardiac conditions, these combinations and methods, by virtue of theiraction as antiatherosclerotic, antianginals, antihypertensives andantihyperlipidemics, are useful in the management of cardiac risk.

The utility of the compounds of the present invention as medical agentsin the treatment of atherosclerosis in mammals (e.g. humans) isdemonstrated by the activity of the compounds of this invention inconventional assays and the clinical protocol described below:

Effect of Amlodipine and Atorvastatin, Alone and in Combination, on theTreatment of Atherosclerosis

This study is a prospective randomized evaluation of the effect of acombination of amlodipine and atorvastatin on the progression/regressionof coronary and carotid artery disease. The study is used to show that acombination of amlodipine and atorvastatin is effective in slowing orarresting the progression or causing regression of existing coronaryartery disease (CAD) as evidenced by changes in coronary angiography orcarotid ultrasound, in subjects with established disease.

This study is an angiographic documentation of coronary artery diseasecarried out as a double-blind, placebo-controlled trial of a minimum ofabout 500 subjects and preferably of about 780 to about 1200 subjects.It is especially preferred to study about 1200 subjects in this study.Subjects are admitted into the study after satisfying certain entrycriteria set forth below.

Entry criteria: Subjects accepted for entry into this trial must satisfycertain criteria. Thus the subject must be an adult either male orfemale, aged 18-80 years of age in whom coronary angiography isclinically indicated. Subjects will have angiographic presence of asignificant focal lesion such as 30% to 50% on subsequent evaluation byquantitative coronary angiography (QCA) in a minimum of one segment(non-PTCA, non-bypassed or non-Ml vessel) that is judged not likely torequire intervention over the next 3 years. It is required that thesegments undergoing analysis have not been interfered with. Sincepercutaneous transluminal cardiac angioplasty (PTCA) interferes withsegments by the insertion of a balloon catheter, non-PTCA segments arerequired for analysis. It is also required that the segments to beanalyzed have not suffered a thrombotic event, such as a myocardialinfarct (MI). Thus the requirement for non-Mi vessels. Segments thatwill be analyzed include: left main, proximal; mid and distal leftanterior descending, first and second diagonal branch, proximal anddistal left circumflex, first or largest space obtuse marginal,proximal, mid and distal right coronary artery. Subjects will have anejection fraction of greater than 30% determined by catheterization orradionuclide ventriculography or ECHO cardiogram at the time of thequalifying angiogram or within the previous three months of theacceptance of the qualifying angiogram provided no intervening eventsuch as a thrombotic event or procedure such as PTCA has occurred.

Generally, due to the number of patients and the physical limitations ofany one facility, the study is carried out at multiple sites. At entryinto the study, subjects undergo quantitative coronary angiography aswell as B-mode carotid artery ultrasonography and assessment of carotidarterial compliance at designated testing centers. This establishesbaselines for each subject. Once admitted into the test, subjects arerandomized to receive amlodipine besylate (10 mgs) and placebo oratorvastatin calcium (80 mgs) and placebo or amlodipine besylate (10mgs) and atorvastatin calcium (80 mgs). All doses set forth in thisprotocol are per day doses. The amount of amlodipine besylate may bevaried as required. Generally, a subject will start out taking 10 mg andthe amount will be titrated down to as little as 5 mg as determined bythe clinical physician. The amount of atorvastatin calcium willsimilarly be titrated down from 80 mg it is determined by the physicianto be in the best interests of the subject. It will be recognized by askilled person that the free base form or other salt forms of amlodipinebesylate or the free base form or other salt forms of atorvastatincalcium may be used in this invention. Calculation of the dosage amountfor these other forms of atorvastatin calcium and amlodipine besylate iseasily accomplished by performing a simple ratio relative to themolecular weights of the species involved.

The subjects are monitored for a one to three year period, generallythree years being preferred. B-mode carotid ultrasound assessment ofcarotid artery atherosclerosis and compliance are performed at regularintervals throughout the study.

Generally, six month intervals are suitable. Typically this assessmentis performed using B-mode ultrasound equipment. However, a personskilled in the art may use other methods of performing this assessment.Coronary angiography is performed at the conclusion of the one to threeyear treatment period. The baseline and post-treatment angiograms andthe intervening carotid artery B-mode ultrasonograms am evaluated fornew lesions or progression of existing atherosclerotic lesions. Arterialcompliance measurements are assessed for changes from baseline and overthe 6-month evaluation periods.

The primary objective of this study is to show that the combination ofamlodipine or pharmaceutically acceptable acid addition salts thereofand atorvastatin or pharmaceutically acceptable salts thereof reducesthe progression of atherosclerotic lesions as measured by quantitativecoronary angiography (QCA) in subjects with clinical coronary arterydisease. QCA measures the opening in the lumen of the arteries measured.

The primary endpoint of the study is the change in the average meansegment diameter of the coronary artery tree. Thus, the diameter of anarterial segment is measured at various portions along the length ofthat segment. The average diameter of that segment is then determined.After the average segment diameter of many segments has been determined,the average of all segment averages is determined to arrive at theaverage mean segment diameter. The mean segment diameter of subjectstaking atorvastatin or pharmaceutically acceptable salts thereof andamlodipine or pharmaceutically acceptable acid addition salts thereofwill decline more slowly, will be halted completely, or there will be anincrease in the mean segment diameter. These results represent slowedprogression of atherosclerosis, halted progression of atherosclerosisand regression of atherosclerosis, respectively.

The secondary objective of this study is to show that the combination ofamlodipine or a pharmaceutically acceptable acid addition salt thereofand atorvastatin or a pharmaceutically salt thereof reduces the rate ofprogression of atherosclerosis in the carotid arteries as measured bythe slope of the maximum intimal-medial thickness measurements averagedover 12 separate wall segments (Mean Max) as a function of time, morethan does amlodipine or a pharmaceutically acceptable acid addition saltthereof or atorvastatin or a pharmaceutically acceptable salt thereofalone. The intimal-medial thickness of subjects taking atorvastatin or apharmaceutically acceptable salt thereof and amlodipine or apharmaceutically acceptable acid addition salt thereof will increasemore slowly, will cease to increase or will decrease. These resultsrepresent slowed progression of atherosclerosis, halted progression ofatherosclerosis and regression of atherosclerosis, respectively.

The utility of the compounds of the present invention as medical agentsin the treatment of angina pectoris in mammals (e.g., humans) isdemonstrated by the activity of the compounds of this invention inconventional assays and the clinical protocol described below:

Effect of Amlodipine and Atorvastatin, Alone and in Combination, on theTreatment of Angina

This study is a double blind, parallel arm, randomized study to show theeffectiveness of amlodipine or pharmaceutically acceptable acid additionsalts thereof and atorvastatin or pharmaceutically acceptable saltsthereof given in combination in the treatment of symptomatic angina.

Entry criteria: Subjects are males or females between 16 and 80 years ofage with a history of typical chest pain associated with one of thefollowing objective evidences of cardiac ischemia: (1) stress testsegment elevation of about one millimeter or more from the ECG; (2)positive treadmill stress test; (3) new wall motion abnormality onultrasound; or (4) coronary angiogram with a significant qualifyingstenosis. Generally a stenosis of about 30-50% is considered to besignificant.

Each subject is evaluated for about ten to thirty-two weeks. At leastten weeks are generally required to complete the study. Sufficientsubjects are used in this screen to ensure that about 200 to 800subjects and preferably about 400 subject are evaluated to complete thestudy. Subjects are screened for compliance with the entry criteria, setforth below, during a four week run in phase. After the screeningcriteria are met, subjects are washed out from their currentanti-anginal medication and stabilized on a long acting nitrate such as,for example, nitroglycerin, isosorbide-5-mononitrate or isosorbidedinitrate. The term “washed out”, when used in connection with thisscreen, means the withdrawal of current anti-anginal medication so thatsubstantially all of said medication is eliminated from the body of thesubject. A period of eight weeks is preferably allowed for both the washout period and for the establishment of the subjection stable doses ofsaid nitrate. Subjects having one or two attacks of angina per weekwhile on stable doses of long acting nitrate are generally permitted toskip the wash out phase. After subjects are stabilized on nitrates, thesubjects enter the randomization phase provided the subjects continue tohave either one or two angina attacks per week. In the randomizationphase, the subjects are randomly placed into one of the four arms of thestudy set forth below. After completing the wash out phase, subjects incompliance with the entry criteria undergo twenty four hour ambulatoryelectrocardiogram (ECG) such as Holter monitoring, exercise stresstesting such as a treadmill and evaluation of myocardial perfusion usingPET (photon emission tomography) scanning to establish a baseline foreach subject. When conducting a stress test, the speed of the treadmilland the gradient of the treadmill can be controlled by a technician. Thespeed of the treadmill and the angle of the gradient are generallyincreased during the test. The time intervals between each speed andgradient increase is generally determined using a modified BruceProtocol.

After the baseline investigations have been completed, subjects areinitiated on one of the following four arms of the study, (1) placebo;(2) atorvastatin calcium (about 2.5 mg to about 160 mg); (3) amlodipinebesylate (about 2.5 mg to about 20 mg); or (4) a combination of theabove doses of amlodipine besylate and atorvastatin calcium together.The subjects are then monitored for two to twenty four weeks. It will berecognized by a skilled person that the free base form or other saltforms of amlodipine besylate or the free base form or other salt formsof atorvastatin calcium may be used in this invention. Calculation ofthe dosage amount for these other forms of atorvastatin calcium andamlodipine besylate is easily accomplished by performing a simple ratiorelative to the molecular weights of the species involved.

After the monitoring period has ended, subjects will undergo thefollowing investigations: (1) twenty four hour ambulatory ECG, such asHolter monitoring; (2) exercise stress testing (e.g. treadmill usingsaid modified Bruce Protocol; and (3) evaluation of myocardial perfusionusing PET scanning. Patients keep a diary of painful ischemic events andnitroglycerine consumption. It is generally desirable to have anaccurate record of the number of anginal attacks suffered by the patientduring the duration of the test. Since a patient generally takesnitroglycerin to ease the pain of an anginal attack, the number of timesthat the patient administers nitroglycerine provides a reasonablyaccurate record of the number of anginal attacks.

To demonstrate the effectiveness of the drug combination of thisinvention, and to determine the dosage amounts of the drug combinationof this invention, the person conducting the test will evaluate thesubject using the tests described. Successful treatment will yield fewerinstances of ischemic events as detected by ECG, will allow the subjectto exercise longer or at a higher intensity level on the treadmill, orto exercise without pain on the treadmill, or will yield betterperfusion or fewer perfusion defects on photoemission tomography (PET).

The utility of the compounds of the present invention as medical agentsin the treatment of hypertension and hyperlipidemia in mammals (e.g.,humans) suffering from a combination of hypertension and hyperlipidemiais demonstrated by the activity of the compounds of this invention inconventional assays and the clinical protocol described below:

Effect of Amlodipine and Atorvastatin, Alone and in Combination, on theTreatment of Subjects Having Both Hypertension and Hyperlipidemia

This study is a double blind, parallel arm, randomized study to show theeffectiveness of amlodipine or pharmaceutically acceptable acid additionsalts thereof and atorvastatin or pharmaceutically acceptable saltsthereof given in combination in controlling both hypertension andhyperlipidemia in subjects who have mild, moderate, or severehypertension and hyperlipidemia.

Each subject is evaluated for 10 to 20 weeks and preferably for 14weeks. Sufficient subjects are used in this screen to ensure that about400 to 800 subjects are evaluated to complete the study.

Entry criteria: Subjects are male or female adults between 18 and 80years of age having both hyperlipidemia and hypertension. The presenceof hyperlipidemia is evidenced by evaluation of the low densitylipoprotein (LDL) level of the subject relative to certain positive riskfactors. If the subject has no coronary heart disease (CHD) and has lessthan two positive risk factors, then the subject is considered to havehyperlipidemia if the LDL of the subject is greater than or equal to190. If the subject has no CHD and has two or more positive riskfactors, then the subject is considered to have hyperlipidemia if theLDL of the subject is greater than or equal to 160. If the subject hasCHD, then the subject is considered to have hyperlipidemia if the LDL ofthe subject is greater than or equal to 130.

Positive risk factors include (1) male over 45, (2) female over 55wherein said female is not undergoing hormone replacement therapy (HRT),(3) family history of premature cardiovascular disease, (4) the subjectis a current smoker, (5) the subject has diabetes, (6) an HDL of lessthan 45, and (7) the subject has hypertension. An HDL of greater than 60is considered a negative risk factor and will offset one of the abovementioned positive risk factors.

The presence of hypertension is evidenced by a sitting diastolic bloodpressure (BP) of greater than 90 or sitting systolic BP of greater than140. All blood pressures are generally determined as the average ofthree measurements taken five minutes apart.

Subjects are screened for compliance with the entry criteria set forthabove. After all screening criteria are met, subjects are washed outfrom their current antihypertensive and lipid lowering medication andare placed on the NCEP ATP II Step 1 diet The NCEP ATP II (adulttreatment panel, 2nd revision) Step 1 diet sets forth the amount ofsaturated and unsaturated fat which can be consumed as a proportion ofthe total caloric intake. The term “washed out” where used in connectionwith this screen means the withdrawal of current antihypertensive andlipid lowering medication so the substantially all of said medication iseliminated from the body of the subject. Newly diagnosed subjectsgenerally remain untreated until the test begins. These subjects arealso placed on the NCEP Step 1 diet. After the four week wash out anddiet stabilization period, subjects undergo the following baselineinvestigations: (1) blood pressure and (2) fasting lipid screen. Thefasting lipid screen determines baseline lipid levels in the fastingstate of a subject. Generally, the subject abstains from food for twelvehours, at which time lipid levels are measured.

After the baseline investigations are performed subjects are started onone of the following: (1) a fixed dose of amlodipine besylate, generallyabout 2.5 to 10 mg; (2) a fixed dose of atorvastatin calcium, generallyabout 10 to 80 mg; or (3) a combination of the above doses of amlodipinebesylate and atorvastatin calcium together. Subjects remain on thesedoses for a minimum of six weeks, and generally for no more than eightweeks. It will be recognized by a skilled person that the free base formor other salt forms of amlodipine besylate or the free base form orother salt forms of atorvastatin calcium may be used in this invention.Calculation of the dosage amount for these other forms of atorvastatincalcium and amlodipine besylate is easily accomplished by performing asimple ratio relative to the molecular weights of the species involved.The subjects return to the testing center at the conclusion of the sixto eight weeks so that the baseline evaluations can be repeated. Theblood pressure of the subject at the conclusion of the study is comparedwith the blood pressure of the subject upon entry. The lipid screenmeasures the total cholesterol, LDL-cholesterol, HDL-cholesterol,triglycerides, apoB, VLDL (very low density lipoprotein) and othercomponents of the lipid profile of the subject. Improvements in thevalues obtained after treatment relative to pretreatment values indicatethe utility of the drug combination.

The utility of the compounds of the present invention as medical agentsin the management of cardiac risk in mammals (e.g., humans) at risk foran adverse cardiac event is demonstrated by the activity of thecompounds of this invention in conventional assays and the clinicalprotocol described below.

Effects of Amlodipine and Atorvastatin, Alone and in Combination, onSubjects at Risk of Future Cardiovascular Events

This study is a double blind, parallel arm, randomized study to show theeffectiveness of amlodipine or pharmaceutically acceptable acid additionsalts thereof and atorvastatin or pharmaceutically acceptable saltsthereof given in combination are effective in reducing the overallcalculated risk of future events in subjects who are at risk for havingfuture cardiovascular events. This risk is calculated by using theFramingham Risk Equation. A subject is considered to be at risk ofhaving a future cardiovascular event if that subject is more than onestandard deviation above the mean as calculated by the Framingham RiskEquation. The study is used to evaluate the efficacy of a fixedcombination of amlodipine and atorvastatin in controlling cardiovascularrisk by controlling both hypertension and hyperlipidemia in patients whohave both mild to moderate hypertension and hyperlipidemia.

Each subject is evaluated for 10 to 20 weeks and preferably for 14weeks. Sufficient subjects are recruited to ensure that about 400 to 800subjects are evaluated to complete the study.

Entry criteria: Subjects included in the study are male or female adultsubjects between 18 and 80 years of age with a baseline five year riskwhich risk is above the median for said subjects age and sex, as definedby the Framingham Heart Study, which is an ongoing prospective study ofadult men and women showing that certain risk factors can be used topredict the development of coronary heart disease; The age, sex,systolic and diastolic blood pressure, smoking habit, presence orabsence of carbohydrate intolerance, presence or absence of leftventricular hypertrophy, serum cholesterol and high density lipoprotein(HDL) of more than one standard deviation above the norm for theFramingham Population are all evaluated in determining whether a patientis at risk for adverse cardiac event. The values for the risk factorsare inserted into the Framingham Risk equation and calculated todetermine whether a subject is at risk for a future cardiovascularevent.

Subjects are screened for compliance with the entry criteria set forthabove. After all screening criteria are met, patients are washed outfrom their current antihypertensive and lipid lowering medication andany other medication which will impact the results of the screen. Thepatients are then placed on the NCEP ATP II Step 1 diet, as describedabove. Newly diagnosed subjects generally remain untreated until thetest begins. These subjects are also placed on the NCEP ATP II Step 1diet. After the four week wash out and diet stabilization period,subjects undergo the following baseline investigations: (1) bloodpressure; (2) fasting; (3) lipid screen; (4) glucose tolerance test; (5)ECG; and (6) cardiac ultrasound. These tests are carried out usingstandard procedures well known to persons skilled in the art. The ECGand the cardiac ultrasound are generally used to measure the presence orabsence of left ventricular hypertrophy.

After the baseline investigations are performed patients will be startedon one of the following: (1) a fixed dose of amlodipine (about 2.5 to 10mg); (2) a fixed dose of atorvastatin (about 10 to 80 mg); or (3) thecombination of the above doses of amlodipine and atorvastatin. It willbe recognized by a skilled person that the free base form or other saltforms of amlodipine besylate or the free base form or other salt formsof atorvastatin calcium may be used in this invention. Calculation ofthe dosage amount for these other forms of atorvastatin calcium andamlodipine besylate is easily accomplished by performing a simple ratiorelative to the molecular weights of the species involved. Patients arekept on these doses and are asked to return in six to eight weeks sothat the baseline evaluations can be repeated. At this time the newvalues are entered into the Framingham Risk equation to determinewhether the subject has a lower, greater or no change in the risk offuture cardiovascular event.

The above assays demonstrating the effectiveness of amlodipine orpharmaceutically acceptable acid addition salts thereof and atorvastatinor pharmaceutically acceptable salts thereof in the treatment of anginapectoris, atherosclerosis, hypertension and hyperlipidemia together, andthe management of cardiac risk, also provide a means whereby theactivities of the compounds of this invention can be compared betweenthemselves and with the activities of other known compounds. The resultsof these comparisons are useful for determining dosage levels inmammals, including humans, for the treatment of such diseases.

The following dosage amounts and other dosage amounts set forthelsewhere in the specification and in the appendant claims are for anaverage human subject having a weight of about 65 kg to about 70 kg. Theskilled practitioner will readily be able to determine the dosage amountrequired for a subject whose weight falls outside the 65 kg to 70 kgrange, based upon the medical history of the subject and the presence ofdiseases, e.g., diabetes, in the subject. All doses set forth herein,and in the appendant claims, are daily doses.

In general, in accordance with this invention, amlodipine besylate isgenerally administered in a dosage of about 2.5 mg to about 20 mg.Preferably, amlodipine besylate is administered in a dosage of about 5mg to about 10 mg. It will be recognized by a skilled person that thefree base form or other salt forms of amlodipine besylate may be used inthis invention. Calculation of the dosage amount for these other formsof or the free base form or other salt forms of amlodipine besylate iseasily accomplished by performing a simple ratio relative to themolecular weights of the species involved.

In general, in accordance with this invention, atorvastatin isadministered in a dosage of about 2.5 mg to about 160 mg. Preferably,atorvastatin is administered in a dosage of about 10 mg to about 80 mg.It will be recognized by a skilled person that the free base form orother salt forms of atorvastatin calcium may be used in this invention.Calculation of the dosage amount for these other forms of or the freebase form or other salt forms of atorvastatin calcium is easilyaccomplished by performing a simple ratio relative to the molecularweights of the species involved.

The compounds of the present invention are generally administered in theform of a pharmaceutical composition comprising at least one of thecompounds of this invention together with a pharmaceutically acceptablecarrier or diluent. Thus, the compounds of this invention can beadministered either individually or together in any conventional oral,parenteral or transdermal dosage form.

For oral administration a pharmaceutical composition can take the formof solutions, suspensions, tablets, pills, capsules, powders, and thelike. Tablets containing various excipients such as sodium citrate,calcium carbonate and calcium phosphate are employed along with variousdisintegrants such as starch and preferably potato or tapioca starch andcertain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type are also employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection also includelactose or milk sugar as well as high molecular weight polyethyleneglycols. When aqueous suspensions and/or elixirs are desired for oraladministration, the compounds of this invention can be combined withvarious sweetening agents, flavoring agents, coloring agents,emulsifying agents and/or suspending agents, as we as such diluents aswater, ethanol, propylene glycol, glycerin and various like combinationsthereof.

The combination of this invention may also be administered in acontrolled release formulation such as a slow release or a fast releaseformulation. Such controlled release dosage formulations of thecombination of this invention may be prepared using methods well knownto those skilled in the art. The method of preferred administration willbe determined by the attendant physician or other person skilled in theart after an evaluation of the subject's condition and requirements. Thegenerally preferred formulation of amlodipine is Norvasc®. The generallypreferred formulation of atorvastatin is Lipitor®.

For purposes of parenteral administration, solutions in sesame or peanutoil or in aqueous propylene glycol can be employed, as well as sterileaqueous solutions of the corresponding water-soluble salts. Such aqueoussolutions may be suitably buffered, if necessary, and the liquid diluentfirst rendered isotonic with sufficient saline or glucose. These aqueoussolutions are especially suitable for intravenous, intramuscular,subcutaneous and intraperitoneal injection purposes. In this connection,the sterile aqueous media employed are all readily obtainable bystandard techniques well-known to those skilled in the art.

Methods of preparing various pharmaceutical compositions with a certainamount of active ingredient are known, or will be apparent in light ofthis disclosure, to those skilled in this art. For examples, seeRemington's Pharmaceutical Sciences, Mack Publishing Company, Easter,Pa., 15th Edition (1975).

Pharmaceutical compositions according to the invention may contain0.1%-95% of the compound(s) of this invention, preferably 1%-70%. In anyevent, the composition or formulation to be administered will contain aquantity of a compound(s) according to the invention in an amounteffective to treat the condition or disease of the subject beingtreated.

Since the present invention relates to the treatment of diseases andconditions with a combination of active ingredients which may beadministered separately, the invention also relates to combiningseparate pharmaceutical compositions in kit form. The kit includes twoseparate pharmaceutical compositions: amlodipine or a pharmaceuticallyacceptable acid addition salt thereof and atorvastatin or apharmaceutically acceptable salt thereof. The kit includes containermeans for containing the separate compositions such as a divided bottleor a divided foil packet, however, the separate compositions may also becontained within a single, undivided container. Typically the kitincludes directions for the administration of the separate components.The kit form is particularly advantageous when the separate componentsare preferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals or whentitration of the individual components of the combination is desired bythe prescribing physician.

It should be understood that the invention is not limited to theparticular embodiments described herein, but that various changes andmodifications may be made without departing from the spirit and scope ofthis novel concept as defined by the following claims.

1. A single pharmaceutical composition comprising: an amount ofamlodipine or a pharmaceutically acceptable acid addition salt thereof;an amount of atorvastatin or a pharmaceutically acceptable salt thereof;and a pharmaceutically acceptable carrier or diluent.
 2. Apharmaceutical composition of claim 1 comprising amlodipine besylate. 3.A pharmaceutical composition of claim 2 comprising the hemicalcium saltof atorvastatin. 4-117. (canceled)
 118. The pharmaceutical compositionof claim 1 comprising the hemicalcium salt of atorvastatin.
 119. Thepharmaceutical composition of claim 1 wherein said atorvastatin ispresent in an amount from about 2.5 mg to about 160 mg.
 120. Thepharmaceutical composition of claim 1 wherein said atorvastatin ispresent in an amount from about 10 mg to about 80 mg.
 121. Thepharmaceutical composition of claim 2 wherein said amlodipine besylateis present in an amount from about 2.5 mg to about 20 mg.
 122. Thepharmaceutical composition of claim 2 wherein said amlodipine besylateis present in an amount from about 5 mg to about 10 mg.
 123. Thepharmaceutical composition of claim 2 wherein said atorvastatin ispresent in an amount from about 2.5 mg to about 160 mg and saidamlodipine besylate is present in an amount from about 2.5 mg to about20 mg.
 124. The pharmaceutical composition of claim 3 wherein saidhemicalcium salt of atorvastatin is present in an amount from about 2.5mg to about 160 mg.
 125. The pharmaceutical composition of claim 3wherein said hemicalcium salt of atorvastatin is present in an amountfrom about 10 mg to about 80 mg.
 126. The pharmaceutical composition ofclaim 3 wherein said hemicalcium salt of atorvastatin is present in anamount from about 2.5 mg to about 160 mg and said amlodipine besylate ispresent in an amount from about 2.5 mg to about 20 mg.
 127. Thepharmaceutical composition of claim 3 wherein said hemicalcium salt ofatorvastatin is present in an amount from about 10 mg to about 80 mg andsaid amlodipine besylate is present in an amount from about 5 mg toabout 10 mg.
 128. The pharmaceutical composition of claim 1 wherein saidamlodipine or said pharmaceutically acceptable acid addition saltthereof occurs as a hydrate or a solvate.
 129. The pharmaceuticalcomposition of claim 1 wherein said atorvastatin or saidpharmaceutically acceptable acid addition salt thereof occurs as ahydrate or a solvate.
 130. The pharmaceutical composition of claim 1wherein said pharmaceutical composition is in the form of a tablet andcomprises at least one excipient, at least one disintegrant, and atleast one binding agent.
 131. The pharmaceutical composition of claim130 wherein said excipient is selected from the group consisting ofsodium citrate, calcium carbonate, and calcium phosphate.
 132. Thepharmaceutical composition of claim 130 wherein said disintegrant ispotato starch or tapioca starch.
 133. A pharmaceutical composition ofclaim 130 wherein said binding agent is selected from the groupconsisting of polyvinylpyrrolidone, sucrose, gelatin, and acacia.
 134. Apharmaceutical composition of claim 130 wherein said tablet comprises atleast one lubricating agent.
 135. The pharmaceutical composition ofclaim 1 further comprising an excipient.
 136. The pharmaceuticalcomposition of claim 135 wherein the excipient is calcium carbonate.137. The pharmaceutical composition of claim 1 further comprising adisintegrant.
 138. The pharmaceutical composition of claim 137 whereinthe disintegrant is starch.
 139. A pharmaceutical composition of claim 1wherein said pharmaceutical composition is in the form of an aqueoussuspension and comprises at least one sweetening agent, at least oneflavoring agent, at least one coloring agent, at least one emulsifyingagent, and at least one suspending agent.
 140. A pharmaceuticalcomposition of claim 135 wherein said diluent is selected from the groupconsisting of water, ethanol, propylene glycol, and glycerin.
 141. Apharmaceutical composition of claim 1 in a form suitable for oraladministration comprising a solution, suspension, tablet, pill, capsuleor powder containing atorvastatin or a pharmaceutically acceptable saltthereof in an amount from about 2.5 mg to about 160 mg and amlodipine ora pharmaceutically acceptable acid addition salt thereof in an amountfrom about 2.5 mg to about 20 mg.
 142. A pharmaceutical composition ofclaim 137 containing from about 5 mg to about 10 mg amlodipine besylateand from about 10 mg to about 80 mg of the hemicalcium salt ofatorvastatin.
 143. A pharmaceutical composition of claim 1 in the formof a tablet containing from about 5 mg to about 10 mg amlodipinebesylate, from about 10 mg to about 80 mg of the hemicalcium salt ofatorvastatin, at least one excipient, at least one disintegrant, atleast one lubricating agent and at least one binding agent.
 144. Apharmaceutical composition of claim 139 in the form of a controlledrelease formulation.
 145. The pharmaceutical composition of claim 1comprising amlodipine mesylate.
 146. The pharmaceutical composition ofclaim 1 comprising amlodipine maleate.
 147. The pharmaceuticalcomposition of claim 1 comprising amlodipine tosylate.